Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF

Nature. 1995 Aug 10;376(6540):524-7. doi: 10.1038/376524a0.


Tyrosine kinase receptors stimulate the Ras signalling pathway by enhancing the activity of the SOS nucleotide-exchange factor. This occurs, at least in part, by the recruitment of an SOS-GRB2 complex to Ras in the plasma membrane. Here we describe a different signalling pathway to Ras that involves activation of the Ras-GRF exchange factor in response to Ca2+ influx. In particular, we show that the ability of Ras-GRF to activate Ras in vivo is markedly enhanced by raised Ca2+ concentrations. Activation is mediated by calmodulin binding to an IQ motif in Ras-GRF, because substitutions in conserved amino acids in this motif prevent both calmodulin binding to Ras-GRF and Ras-GRF activation in vivo. So far, full-length Ras-GRF has been detected only in brain neurons. Our findings implicate Ras-GRF in the regulation of neuronal functions that are influenced by Ca2+ signals.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Brain-Derived Neurotrophic Factor
  • Calcium / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Calmodulin / metabolism
  • Cell Line
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • Enzyme Activation / drug effects
  • Guanine Nucleotide Exchange Factors
  • Ionomycin / pharmacology
  • Membrane Potentials
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Molecular Sequence Data
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • Protein Binding
  • Proteins / metabolism*
  • Rats
  • Signal Transduction
  • Transfection
  • ras Guanine Nucleotide Exchange Factors
  • ras Proteins / genetics
  • ras Proteins / metabolism*
  • ras-GRF1


  • Brain-Derived Neurotrophic Factor
  • Calmodulin
  • Guanine Nucleotide Exchange Factors
  • Nerve Tissue Proteins
  • Proteins
  • ras Guanine Nucleotide Exchange Factors
  • ras-GRF1
  • Ionomycin
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • ras Proteins
  • Calcium